Anatomic location of the first dorsal extensor compartment for surgical De-Quervain's tenosynovitis release: A cadaveric study.

BACKGROUND: De-Quervain's tenosynovitis is a disorder arising from the compression and irritation of the first dorsal extensor compartment of the wrist. Patients who fail conservative treatment modalities are candidates for surgical release. However, risks with surgery include damage to the superficial radial nerve and an incomplete release due to inadequate dissection. Currently, there is a paucity of literature demonstrating the exact anatomic location of the first dorsal extensor compartment in reference to surface anatomy. Thus, this cadaveric study was performed to determine the exact location of the first extensor compartment and to devise a reliable surgical incision to prevent complications. AIM: To describe the location of the first dorsal compartment in relation to bony surface landmarks to create replicable surgical incisions. METHODS: Six cadaveric forearms, including four left and two right forearm specimens were dissected. Dissections were performed by a single fellowship trained upper extremity orthopaedic surgeon. Distance of the first dorsal compartment from landmarks such as Lister's tubercle, the wrist crease, and the radial styloid were calculated. Other variables studied included the presence of the superficial radial nerve overlying the first dorsal compartment, additional compartment sub-sheaths, number of abductor pollicis longus (APL) tendon slips, and the presence of a pseudo-retinaculum. RESULTS: Distance from the radial most aspect of the wrist crease to the extensor retinaculum was 5.14 mm ± 0.80 mm. The distance from Lister's tubercle to the distal aspect of the extensor retinaculum was 13.37 mm ± 2.94 mm. Lister's tubercle to the start of the first dorsal compartment was 18.43 mm ± 2.01 mm. The radial styloid to the initial aspect of the extensor retinaculum measured 2.98 mm ± 0.99 mm. The retinaculum length longitudinally on average was 26.82 mm ± 3.34 mm. Four cadaveric forearms had separate extensor pollicis brevis compartments. The average number of APL tendon slips was three. A pseudo-retinaculum was present in four cadavers. Two cadavers had a superficial radial nerve that crossed over the first dorsal compartment and retinaculum proximally (7.03 mm and 13.36 mm). CONCLUSION: An incision that measures 3 mm proximal from the radial styloid, 2 cm radial from Lister's tubercle, and 5 mm proximal from the radial wrist crease will safely place surgeons at the first dorsal compartment.

Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer.

BACKGROUND: Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. METHODS: To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. RESULTS: Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. CONCLUSIONS: Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.

Adult Isthmic Spondylolisthesis: A Radiographic and Outcomes Analysis Comparing Circumferential Fusions Versus TLIF Procedures.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The objective of this study was to compare radiographic and patient-reported outcome measures (PROMs) between circumferential fusions and transforaminal lumbar interbody fusion (TLIF) for adult isthmic spondylolisthesis (IS). SUMMARY OF BACKGROUND DATA: Definitive management of adult IS typically requires decompression and fusion. Multiple fusion techniques have been described, but literature is sparse in identifying the optimal technique. METHODS: Patients with IS undergoing single-level or 2-level circumferential fusion or TLIF with a minimum 1-year follow-up were included. Patient demographics, surgical characteristics, and PROMs were extracted from patients' electronic medical records. Descriptive statistics and multivariate regression analysis compared outcomes with significance set at P -value <0.05. RESULTS: A total of 78 circumferential fusions (48 open decompression and fusions and 30 circumferential fusions utilizing posterior percutaneous instrumentation) and 50 TLIF procedures were included. Length of stay was significantly longer when comparing circumferential procedures (3.56±0.96 d) versus TLIFs (2.88±1.14 d) ( P =0.002). The circumferential fusion group resulted in greater postoperative improvement in segmental lordosis [anterior/posterior (A/P): 6.45, TLIF: -1.99, P <0.001], posterior disk height (A/P: 12.6 mm, TLIF: 8.9 mm, P <0.001), and ∆disk height (A/P: 7.7 mm, TLIF: 3.6 mm, P <0.001). Both groups significantly improved in all PROMs ( P <0.001). While the circumferential fusion group had a significantly higher rate of perioperative surgical complications (12.82% vs. 2.00%, P =0.049), there was no difference in the rate of 30-day readmissions ( P =0.520) or revision surgeries between techniques ( P =0.057). CONCLUSIONS: Circumferential fusions are associated with improvements in radiographic outcomes compared with TLIFs, but this is at the expense of longer hospital length of stay and increased risk for perioperative complications. The surgical technique did not result in superior postoperative PROMs or differences in readmissions or revisions.

Pancreaticoduodenectomy outcomes for locally advanced right colon cancers: A systematic review.

BACKGROUND: Pancreaticoduodenectomy (PD) with right hemicolectomy (RH) to treat locally advanced right colon cancer (LARCC) has been rarely reported in the literature. Herein, we characterize clinicopathologic factors and evaluate outcomes of en bloc PD and RH for LARCC. METHODS: A systematic review of the literature was conducted on PubMed using MeSH terms ("pancreaticoduodenectomy" or "pancreas/surgery" or "duodenum/surgery" or "colectomy") and ("colonic neoplasms"). Data was extracted from patients who underwent en bloc PD and RH for LARCC. Factors investigated included patient demographics, surgical and pathologic parameters, postoperative complications, disease recurrence, and survival. RESULTS: Our search yielded 27 articles (106 patients), including 1 case from our institution. Most patients were male (62.1%), median age 58 years (range 34-83). Surgical procedures performed included en bloc RH with PD (n = 91, 85.8%) and en bloc RH with pylorus-preserving PD (n = 15, 14.2%). Among reported, 95.5% of patients (n = 63), underwent R0 resection. One or more complications were reported in 33 patients (52.4%). Median survival was 168 months. Survival after resection was 75.9% at 2 years and 66.3% at 5 years. Overall survival was greater in patients with no lymph node involvement (IIC versus IIIC, hazard ratio 8.4, P = .003). Five-year survival for patients was 84.9% in patients with stage IIC versus 46.4% in patients with stage IIIC. There were 3 postoperative mortalities. CONCLUSION: This data demonstrates that en bloc PD and RH is rarely performed yet can be a potentially safe treatment option in patients with LARCC. Lymph node involvement was the only independent prognostic factor.

The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo.

PURPOSE: High-grade gliomas are lethal malignancies that cause morbidity and mortality due to local progression rather than metastatic spread. Our group has previously demonstrated that human GRM1 (hGRM1) is ectopically expressed in melanocytes leading to a transformed phenotype. Riluzole, a glutamate release inhibitor, leads to apoptotic cell death via DNA damage. Recent work has demonstrated the pathological significance of the related mGluR3/GRM3 (protein or gene: hGRM3) in gliomas. We evaluated the effect of riluzole on glioma cells. EXPERIMENTAL DESIGN: Western blot analysis and immunofluorescence was performed to assess for GRM3 expression in commercially available and patient-derived glioma cells and for functional analysis of GRM3 using receptor agonist/antagonists and downstream effectors, ERK and AKT phosphorylation, as the read-out. Glutamate secretion by glioma cells was measured using ELISA. Flank and intracranial mouse xenograft models were used to assess growth delay with the glutamate release inhibitor, riluzole (RIL). Immunofluorescence was used to evaluate 53BP1 or γ-H2AX foci after RIL. RESULTS: GRM3 was expressed in most tested glioma samples, and strongly expressed in some. Glioma cells were found to secrete glutamate in the extracellular space and to respond to receptor stimulation by activating downstream ERK. This signaling was abrogated by pretreatment with RIL. Treatment with RIL caused an increase in DNA damage markers, and an increase in cellular cytotoxicity in vitro and in vivo. CONCLUSIONS: We have demonstrated that pretreatment with the glutamate-release inhibitor riluzole sensitizes glioma cells to radiation and leads to greater cytotoxicity; these results have clinical implications for patients with glioblastoma.

VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells.

PURPOSE: DNA double-strand breaks (DSBs) can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). We demonstrate the selectivity of VX-984, a DNA-PK inhibitor, using assays not previously reported. EXPERIMENTAL DESIGN: The class switch recombination assay (CSR) in primary B cells was used to measure efficiency of NHEJ. A cellular reporter assay (U2OS EJ-DR) was used to assess the efficiency of HR and NHEJ in cells treated with VX-984. Immunofluorescence assays (IF) evaluated γ-H2AX foci for DSB repair kinetics in human astrocytes and T98G glioma cells. Western blotting was used to evaluate phosphorylation of DNA-PKcs substrates. RESULTS: We found a dose-dependent reduction in CSR efficiency with VX-984, and through the EJ-DR assay, dramatic dose-dependent increases in HR and mNHEJ. Immunofluorescence assays showed an inability of malignant cells to resolve γ-H2AX foci in the presence of VX-984. Radiation-induced phosphorylation of DNA-PK substrates was further reduced by treatment with VX-984. CONCLUSIONS: VX-984 efficiently inhibits NHEJ, resulting in compensatory increases in alternative repair pathways, increases DSBs, and appears to affect transformed cells preferentially.

Oncolytic Viruses-Natural and Genetically Engineered Cancer Immunotherapies.

There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.